Hereditary Predisposition to Breast Cancer

Breast cancer is a common malignancy. Hereditary predisposition plays an important role in some patients. Assessing it helps guide surveillance, prevention and, in certain circumstances, treatment of an established cancer.

BRCA1 and BRCA2 encode proteins that repair damaged DNA. Inherited pathogenic or likely pathogenic variants substantially increase breast and ovarian cancer risk. CHEK2 encodes a kinase in the DNA damage response system; associated risk is usually moderate and depends on the variant, family history and other factors. It should not automatically be equated with BRCA1/2 risk.

Who Benefits from Testing

Indications and test selection depend on age at diagnosis, tumor type, personal and family history, ancestry and current recommendations. Testing may benefit affected patients and healthy relatives, particularly when a familial pathogenic variant is known. When possible, family testing starts with an affected relative. Genetic counseling before and after testing is advisable.

Results may inform surgery, drug treatment and surveillance but do not determine them automatically. Not every variant is harmful. A variant of uncertain significance (VUS) should not justify preventive surgery or another treatment change.

Risk and Prevention

Carrying a pathogenic variant means increased risk, not inevitable disease. Risk varies with age, gene, variant and other circumstances. Universal estimates of the proportion of hereditary cases due to BRCA1/2 or CHEK2, or a risk increase beginning strictly after age 42, should not be applied.

For pathogenic BRCA1/2 variant carriers, enhanced surveillance, risk-reducing mastectomy and removal of the fallopian tubes and ovaries at an appropriate age may be discussed. Medication to reduce risk, including tamoxifen, is not suitable for everyone. Decisions require discussion of benefits, complications, reproductive plans and preferences. Detecting any CHEK2 change does not itself indicate removal of the ovaries or breasts: prevention is guided by individual risk.

Limitations of Common-Variant Panels

Variants historically studied in particular populations include BRCA1 4153delA, 4158A>G, 5382insC, 185delAG and 300T>G; BRCA2 695insC and 6174delT; and CHEK2 1100delC. These legacy names must be matched to the laboratory nomenclature. Their frequencies depend on ancestry; the short list does not cover all hereditary cases in Europe or Armenia.

A negative limited panel excludes only the variants tested, not all hereditary predisposition. Indications may warrant more comprehensive testing of other variants or genes. Even a negative expanded test does not remove the need to assess family history or undergo routine cancer screening.